The translatome of Glioblastoma multiforme

Abstract

Abstract Glioblastoma Multiforme (GBM) is the most common and aggressive brain tumor, containing intrinsic resistance to current therapies leading to poor clinical outcomes. Therefore, understanding the underlying mechanisms of GBM is an urgent medical need. Although radiotherapy contributes significantly to patient survival, GBMs recur typically within the initial radiation target volume, suggesting remaining GBM cells are highly radioresistant. Deregulation of the protein translation mechanism has been shown to contribute to cancer progression by driving translational control of specific mRNA transcripts involved in cancer cell regulation. To identify new potential therapeutic targets for the treatment of GBM we pioneered ribosome profiling of glioblastoma sphere cultures (GSCs) under normal and radiotherapeutic conditions. We found that the global translation of genes matched and overlapped with previously published GBM subtypes, based on the transcriptional level. In addition, we revealed a broad spectrum of open reading frame types in both coding and non-coding regions, including a set of lncRNAs and pseudogenes undergoing active translation. In addition, we identified new mRNA transcripts being translated. Finally, we show that translation of histones is inhibited while splicing factors are more intensively translated after irradiation of GSCs. Together, our unprecedented GBM riboprofiling provides new insights in real time protein synthesis in GBM under normal and radiotherapeutic conditions which forms a resource for future research and provides potential new targets for therapy. Teaser We show a pioneering riboprofiling effort of glioblastoma (GBM), which provides new insights in real-time protein synthesis under normal and radiotherapeutic conditions. We found that the global translation of genes matched and overlapped with previously published GBM subtypes, as based on the transcriptional level. In addition, we revealed a broad spectrum of open reading frame types in both coding and non-coding regions, including a set of lncRNAs and pseudogenes undergoing active translation. In addition, we identified new mRNA transcripts being translated. Finally, we show that translation of histones is inhibited while splicing factors are more intensively translated after irradiation of GSCs. Our data form a resource for future research and provides potential new targets for therapy.